November 2017 | Samhain 2017

Combination Therapy for Cystic Fibrosis

Fri, 17 November 17 15:09

Patients with Cystic Fibrosis at St Vincent’s University Hospital took part in a randomised double-blind placebo-controlled phase 3 crossover clinical trial to evaluate the efficacy and safety of ivacaftor alone and in combination with tezacaftor, a CF transmembrane conductance regulator (CFTR).  The multi-centred trial led by the University of Alabama and the University of Arizona evaluated the drug and drug combinations in patients with cystic fibrosis who were heterozygous for the Phe508del mutation and had a CFTR mutation associated with residual CFTR function.  The study, published recently in the New England Journal of Medicine, demonstrated the impact of both tezacaftor-ivacaftor and ivacaftor only treatment in this specific cohort of patients.  A companion trial showed that patients who were homozygous for the Phe508del CFTR mutation also benefited from the combination therapy.  Researchers believe that these combination therapies will extend the number of patients who can benefit from modulator therapies. 

In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, the investigators evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV1) through week 24 (calculated in percentage points); relative change in the percentage of the predicted FEV1 through week 24 (calculated as a percentage) was a key secondary end point.  The combination of tezacaftor and ivacaftor was found to be efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation.  The clinical research participation at St Vincent’s University Hospital was led by Prof Edward McKone, consultant in respiratory medicine and UCD Clinical Professor.

Original Papers

Tezacaftor–Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis 

Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, Nair N, Simard C, Han L, Ingenito EP, McKee C, Lekstrom-Himes J, Davies JC.

N Engl J Med. 2017 Nov 3. doi: 10.1056/NEJMoa1709847 [link]


Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del

Jennifer L. Taylor-Cousar, M.D., Anne Munck, M.D., Edward F. McKone, M.D., Cornelis K. van der Ent, M.D., Ph.D., Alexander Moeller, M.D., Christopher Simard, M.D., Linda T. Wang, M.D., Edward P. Ingenito, M.D., Ph.D., Charlotte McKee, M.D., Yimeng Lu, Ph.D., Julie Lekstrom-Himes, M.D., and J. Stuart Elborn, M.D.

N Engl J Med 2017; 377:2013-2023November 23, 2017DOI: 10.1056/NEJMoa1709846 [link]


About Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that lead to progressive respiratory decline.  More than 2,700 CFTR mutations are known to cause cystic fibrosis.  Some mutant CFTR proteins in approximately 5% of patients with CF show residual function and respond to the CFTR potentiator ivacaftor in vitro whereas ivacaftor alone does not restore activity to the Phe508del mutant CFTR.

Phe508del is the most common CFTR mutation worldwide with approximately 45% of patients with cystic fibrosis homozygous for this allele.  Ireland has the highest incidence of cystic fibrosis in the world and the prevalence of this mutation in the Irish population is 56%[1].

The Phe508del mutation causes a processing defect that severely reduces the trans-membrane conductor regulator protein at the epithelial membrane and disrupts the ion channel opening for those CFTR proteins that reach the cell surface.  Therapeutic strategies for cystic fibrosis include the provision of a CFTR corrector agent and potentiator therapy which aim to address the underlying cellular processing defect and chloride channel function respectively.